3-hydroxy-3-substituted glutaric acid derivatives

ABSTRACT

3-Hydroxy-3-substituted glutaric acid derivatives are prepared in two steps. An ester of a carboxylic acid is reacted with a 2alkenyl magnesium bromide and the resulting 4-substituted-4hydroxy-1,6-heptadiene is ozonized, then oxidized to form the 3hydroxy-3-substituted glutaric acid. These compounds have antiulcerogenic activity.

United States Patent Baran et al.

[ June 18, 1974 3-HYDROXY-3-SUBSTITUTED GLUTARIC ACID DERIVATIVES Inventors: John Stanislaus Baran, Winnetka;

Donna Langford, Wilmette, both of I11.

Assignee: G. D. Searle & Co., Chicago, 111.

Filed: July 20, 1972 Appl. N0.: 273,417

US. Cl 260/535 P, 260/514 K, 260/521 R, 260/617 R, 260/618 R, 260/638 R, 424/305, 424/308, 424/313 Int. Cl. C07c 59/12 Field of Search 260/535 P References Cited UNITED STATES PATENTS 12/1962 Toulmin 260/53] R Primary EraminerLorraine A. Weinberger Assistant EraminerPaul J. Killos Attorney, Agent, or Firm-Elliot N. Schubert ABSTRACT 8 Claims, No Drawings 3-HYDROXY-3-SUBST1TUTED GLUTARIC ACID DERIVATIVES The present invention is concerned with 3-hydroxy- 3-substituted glutaric acid derivatives of the general formula, I,

wherein R is selected from the group consisting of an alkyl radical, containing more than 1 carbon atom and less than 18 carbon atoms, a cycloalkyl, cycloalkyl(alkyl) or benzyl radical. Typical alkyl radicals are ethyl, n-propyl, isopropyl, 3-butyl, t-butyl, n-decyl, pentadecyl, and the corresponding monovalent, saturated, acyclic-or branched-chain, hydrocarbon groupings of empirical formula C H where n is greater than I and less than 18. Cyclohexyl is a typical cycloalkyl radical of empirical formula C H and cyclopentylmethyl is an example of a cycloalkyl(alkyl) radical of empirical formula C,.H, These compounds are prepared by the method shown in Scheme A.

Alkyl esters of carboxylic acids are reacted with 2- alkenyl magnesium bromides to form l,7-substituted 4- substituted-4-hydroxy-l,7-heptadienes, where R and R" are hydrogen or lower alkyl. The dienes are ozonized, then oxidized to provide 3-hydroxy-3-substituted glutaric acids. Thus, ethyl cyclohexanecarboxylate is converted to 4-cyclohexyl-4-hydroxy-l,6-heptadiene by reaction with allyl magnesium bromide, and ozonolysis followed by oxidation in acidic hydrogen peroxide provides 3-hydroxy-3cyclohexylglutaric acid.

The compounds of the present invention have valuable pharmacological properties. A manifestation of this pharmacological utility is the anti-ulcerogenic activity demonstrated by standardized tests designed to detect that activity. 3-Hydroxy-3methylglutaric acid, which is described in US. Pat. No. 3,070,512, does not exhibit anti-ulcerogenic acitvity.

The anti-ulcerogenic utility of the instant compounds is evident from the results of a standardized test designed to detect the substances which inhibit the ulceration reported by Shay et al., Gastro-enterology, 5, 43

( 1945) to occur in rats subjected to fasting and pyloric ligation. in this test, male Charles River rats weighing 200-250 gm. are fasted 72 hr. prior to ligation. Immediately following ligation, the prescribed dose of compound, dissolved or suspended in 1.0 ml. of pH 2.0 hydrochloric acid, is intragastrically administered to each of a group of 6 animals. A like group of animals to which is identically and concurrently administered the acid alone serves as controls. Precisely 19 hours later, the stomachs of surviving animals are excised and examined under 5X magnification. The number of ulcers occurring in the non-secretory portion of each stomach is counted in 4 groups according to size 2 mm., 2-4 mm. 4-8 mm., and 8 mm.); and each rat receives a score, 1, which is a weighted average of the logarithms of the ulcer counts in the several size groups, determined by a formula found approximately optimal by discriminant function analysis to be Z=20.00 log (N +l )+0.22 log. (N +l )+46.76 log where N; N, are the observed ulcer counts of the increasing size groups. Since long-term studies in approximately 400 animals shows that the average 2 value for controls is 96.2, with a standard error per group of 6 equal to 18.97, a decrease in the average 2 score for a given test group, relative to concurrent controls, amounting to 37.5 or more is significant (P g 0.05) and a compound producing such a decrease is considered anti-ulcerogenic.

The invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only and it will be understood that the invention is not to be construed as limiting either in spirit or in scope by the details contained therein, as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples temperatures are given in degrees centigrade (C.). Quantities of materials are expressed in parts by weight unless otherwise noted. Pressure is indicated in millimeters (mm.) of mercury.

EXAMPLE I To. 500 parts by volume of ether containing parts of allyl magnesium bromide is slowly added, with stirring, 40 parts of ethyl cyclohexanecarboxylate, dis solved in parts by volume of tetrahydrofuran. The reaction mixture is then cooled and a saturated ammonium chloride solution is slowly added while the solution is continuously stirred. 2 N Hydrochloric acid solution is added until all salts are dissolved. The ethereal layer is separated and the aqueous layer is extracted twice with benzene. The organic layers are combined and dried over anhydrous magnesium sulfate. The magnesium sulfate is removed by suction filtration and the organic solvent is removed by evaporation at reduced pressure. Fractional distillation provides 4-cyclohexyl- 4-hydroxy-1,6-heptadiene, boiling at 90 at 1.25 mm.

4.12 parts of 4-cyclohexyl-4-hydroxyl ,G-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to 20C. A stream of ozone is passed through the solution for 25 minutes and the solution is flushed with oxygen. This solution is slowly added to 333 parts by volume of acetic acid. The resulting solution is concentrated to a volume of 40 parts. A solution consisting of 33.3 parts by volume of acetic acid, 30 parts by volume of water, 8.3 parts by volume of 30% hydrogen peroxide, and 0.66 parts of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at 100 and is then cooled to room temperature. The cooled solution is added to a mixture consisting of 0.166 parts of platinum oxide and 50 parts by volume of water over a period of thirty minutes. The resulting mixture is heated at 100 for 2 hours, then allowed tocool to room temperature. 0.67 Parts of barium carbonate is added and the mixture is allowed to stir for 12 hours. This solution is treated with decolorizing charcoal and is filtered. The solvent is removed at reduced pressure and the product is obtained by trituration with chloroform. The product is 3-hydroxy-3-cyclohexylglutaric acid. The formula for this compound is EXAMPLE 2 Using the procedure of Example 1, 40 parts of ethyl palmitate in ISO parts by volume of tetrahydrofuran are added to 49 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4-npentadecyl-4-hydroxy-1,6-heptadiene, boiling at l68-l70 at 0.4 mm.

6.0 Parts of this 1,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to -C. A stream of ozone is passed through this solution for minutes and the ozonized solution is added to 50 parts by volume of acetic acid. This solution is concentrated to parts and a solution of 66 parts by volume of acetic acid, 60 parts by volume of water, 16 parts by volume of an aqueous 30% hydrogen peroxidesolution and 1.32 parts by volume of an aqueous 30%.hydrogen peroxide solution and 1.32 parts by volume of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at 100 and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0.333 parts of platinum oxide and parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature. 1.2 Parts of barium carbonate is added and this mixture is allowed to stir for l2 hours. Isolation and purification, as is described in Example 1, provides 3-hydroxy-3-pentadecylglutaric acid, melting at 74-76. The formula of this compound is EXAMPLE 3 Using the procedure of Example 1, 40 parts of isobutyl isobutyrate in 150 parts by volume of tetrahydrofuran is added to 97 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4'isopropyl- 4-hydroxy-l,6-heptadiene, boiling at 4345 at 1.35

3.0 Parts of this 1,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to 20C. A stream of ozone is passed through this solution for 30 minutes and the ozonized solution is added to 33 parts by volume of acetic acid. This solution is concentrated to 40 parts and a solution of 66 parts by volume of acetic acid, 33 parts by volume of water, 8.3 parts by volume of an aqueous 30% hydrogen peroxide solution, and 0.67 parts by volume of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at 100 and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0. 16 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then ailowed to cool to room temperature. 0.67 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. Isolation and purification, as is described in Example 1, provides 3-hydroxy-3-isopropylglutaric acid. The formula of this compound is EXAMPLE 4 Using the procedure of Example 1, 40 parts of ethyl pentanoate in 150 parts by volume of tetrahydrofuran is added to 108 parts of allyi magnesium bromide in 500 parts by volume of ether to provide 4-n-butyl-4- hydroxy-l ,6-heptadiene, boiling at -92 at 5.8 mm.

3.0 Parts of this 1,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to -20C. A stream of ozone is passed through this solution for 30 minutes and the ozonized solution is added to 30 parts by volume of acetic acid. This solution is concentrated to 40 parts and a solution of 66 parts by volume of acetic acid, 32 parts by volume of water, 8.2 parts by volume of an aqueous 30% hydrogen peroxide solution, and 0.67 parts by volume of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at and is cooled to room temperature. The cooled solution is added to a mixture consisting of 8.16 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature. 0.67 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. isolation and purification, as is described in Example 1, provide 3-hydroxy-3-n-butylglutaric acid. The formula of this compound is EXAMPLE 5 Using the procedure of Example 1, 40 parts of ethyl 2,2-dimethylpropionate in parts by volume of tetrahydrofuran are added to 103 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4-tbutyl-4-hydroxy-l,fi-heptadiene, boiling at 82 at 0.7

31.0 Parts of this 1,6-heptadiene is dissolved in 50 this solution for 30 minutes and the ozonized solution is added to 33 parts by volume of acetic acid. This solution is concentrated to 40 parts and a solution of 33 parts by volume of acetic acid, 32 parts by volume of water, 8.2 parts by volume of an aqueous 30% hydrogen peroxide solution, and 0.67 parts by volume of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at 100 and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0.16 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature. 0.67 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. Isolation and purification, as is described in Example 1, provides 3-hydroxy-3-t-butylglutaric acid. The formula of this compound is EXAMPLE 6 Using the procedure of Example 1, 40 parts of ethyl undecanate in 150 parts by volume of tetrahydrofuran is added to 68 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4-decyl-4-hydroxy- 1,6-heptadiene, boiling at l08-l 12 at 0.3 mm.

4.0 Parts of this 1,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to C. A stream of ozone is passed through this solution for minutes and the ozonized solution is added to 33.2 parts by volume of acetic acid. This solution is concentrated to 40 parts and a solution of 33.2 parts by volume of acetic acid, 30 parts by volume of water, 8.3 parts by volume of an aqueous 30% hydrogen peroxide solution and 0.67 parts by volume of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at 100 and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0. 166 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature. 0.67 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. Isolation and purification, as is described in Example 1, provides 3-hydroxy-3-n-decylglutaric acid. The formu 1 a of this compound is Using the procedure of Example 1, 40 parts of ethyl cyclopentylacetate in 150 parts by volume of tetrahydrofuran are added to 63.7 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4- cyclopentanemethyl-4-hydroxy- 1 ,6-heptadiene, boiling at 145 at 20 mm.

4.0 Parts of this 1,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to 20C. A stream of ozone is passed through this solution for 30 minutes and the ozonized solution is added to 33 parts by volume of acetic acid. This solution is concentrated to 40 parts and a solution of 33 parts by volume of acetic acid, 30 parts by volume of water, 8.3 parts by volume of an aqueous 30% hydrogen peroxide solution, and 0.67 parts by volume of sulfuric acid is added to the concentrate with stirring. This solution is-heated for 2 hours at 100 and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0.16 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature. 0.67 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. Isolation and purification, as is described in Example 1, provides 3-hydroxy-3-cyclopentylmethylglutaric acid, melting at 1 l2-l 14. The formula of the compound is CHz-COZH EXAMPLE 8 Using the procedure of Example 1, 49 parts of ethyl phenylacetate in 150 parts by volume of tetrahydrofuran are added to 108 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4- benzyl-4-hydroxy-1,6-heptadiene, boiling at 153 at 20 3.8 Parts of this 1,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to 60C. A stream of ozone is passed through this solution for 30 minutes and the ozonized solution is added to 30 parts by volume of acetic acid. This solution is concentrated to parts and a solution of 66 parts by volume of acetic acid, 60 parts by volume of water, 30 parts by volume of an aqueous 30% hydrogen peroxide solution, and 1.0 part by volume of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0.200 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature. 1.0 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. Isolation and purification, as is described in Example 1, provides 3-hydroxy-3-benzylglutaric acid. The formula of this compound is EXAMPLE 9 Using the procedure of Example 1, 40 parts of ethyl butyrate in parts by volume of tetrahydrofuran is added to 98 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4-n-propyl-4- hydroxy-1,6-heptadiene, boiling at 70 at 17 mm.

6.0 Parts of this 1,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to -20C. A stream of ozone is passed through this solution for 30 minutes and the ozonized solution is added to 50 parts by volume of acetic acid. This solution is concentrated to 40 parts and a solution of 66 parts by volume of acetic acid, 60 parts by volume of water, 16 parts by volume of an aqueous 30% hydrogen peroxide solution, and L32 parts by volume of sulfuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at 100 and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0.333 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at l for 2 hours, then allowed to cool to room temperature. 1.2 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. isolation and purification, as is described in Example 1, provides 3-hydroxy-3-n-propylglutaric acid. The formula of this compound is EXAMPLE Using the procedure of Example l, 40 parts of ethyl propionate in 150 parts by volume of tetrahydrofuran are added to 103 parts of allyl magnesium bromide in 500 parts by volume of ether to provide 4-ethyl-4- hydroxy-l,6-heptadiene, boiling at 65 at 17 mm.

3L0 Parts of this l,6-heptadiene is dissolved in 50 parts by volume of ethyl acetate and the solution is cooled to 20C. A stream of ozone is passed through this solution for 30 minutes and the ozonized solution is added to 33 parts by volume of acetic acid. This solution is concentrated to 40 parts and a solution of 33 parts by volume of acetic acid, 32 parts by volume of water, 8.2 parts by volume of an aqueous 30% hydrogen peroxide solution, and 0.67 parts by volume of suifuric acid is added to the concentrate with stirring. This solution is heated for 2 hours at 100 and is cooled to room temperature. The cooled solution is added to a mixture consisting of 0. 16 parts of platinum oxide and 50 parts by volume of water. The resulting mixture is heated at 100 for 2 hours, then allowed to cool to room temperature. 0.67 Parts of barium carbonate is added and this mixture is allowed to stir for 12 hours. isolation and purification, as is described in Example 1. provides 3-hydroxy-3-ethylglutaric acid, melting at 97. The formula of this compound is What is claimed is: 1. Compounds of the structural formula ethylglutaric acid. 

2. As in claim 1, the compound which is 3-hydroxy-3-pentadecylglutaric acid.
 3. As in claim 1, the compound which is 3-hydroxy-3-isopropylglutaric acid.
 4. As in claim 1, the compound which is 3-hydroxy-3-butylglutaric acid.
 5. As in claim 1, the compound which is 3-hydroxy-3-t-butylglutaric acid.
 6. As in claim 1, the compound which is 3-hydroxy-3-n-decylglutaric acid.
 7. As in claim 1, the compound which is 3-hydroxy-3-propylglutaric acid.
 8. As in claim 1, the compound which is 3-hydroxy-3-ethylglutaric acid. 